Structure, potency and selectivity of a novel spleen tyrosine kinase inhibitor, RO9021. (A) Compound structure of RO9021, 6-((1R,2S)-2-amino-cyclohexylamino)-4-(5,6-dimethyl-pyridin-2-ylamino)-pyridazine-3-carboxylic acid amide. (B) Inhibition of spleen tyrosine kinase (SYK) enzymatic activity, measured by incorporation of 33P-ATP into SYK substrate peptide. The half-maximal inhibitory concentration (IC50) is reported as the average value of three independent assays. (C) Kinome selectivity of RO9021. RO9021 was profiled against 392 nonmutant kinases by KinomeScan and presented as a kinome dendrogram. Circle size is proportional to percentage inhibition at the test concentration (1 μM): largest circle, 99% inhibition; medium circle, 90 to 99% inhibition; smallest circles, 51 to 90% inhibition. Arrow, SYK kinase (blue circle). (D) Selectivity score of RO9021. The selectivity score is a quantitative measure of compound selectivity, calculated by dividing the number of kinases that compounds bind to by the total number of distinct kinases tested, excluding mutant variants. (E) Structural basis of RO9021 selectivity. Crystal structure of RO9021 bound to SYK. Orange dotted lines, possible hydrophobic interactions between RO9021 and the Pro455/Gly454 region (surface shaded red).
Liao et al. Arthritis Research & Therapy 2013 15:R146 doi:10.1186/ar4329